Periodic Reporting for period 1 - symESTIM (Harnessing spinal electrical stimulation to modulate autonomic function after spinal cord injury)
Período documentado: 2020-03-01 hasta 2022-02-28
Autonomic dysfunction (i.e. the unconscious control of many of the body’s systems) is a top health priority after spinal cord injury (SCI), and cardiovascular issues (i.e. a major autonomic function) are the #1 cause of death. Brief, but severe, decreases and increases in blood pressure are some of the most common effects of autonomic dysfunction after SCI and these issues are well-established risk factors for stroke and heart attack (both of which those with SCI suffer from at an alarming rate). The clinical options for managing swings in blood pressure are limited. Drugs are designed to either increase or decrease blood pressure, and most last hours to a full day, meaning that clinically managing blood pressure in those with SCI is extremely difficult. New technology capable of electrically stimulating the spinal cord, or “neuroprosthetics”, has become a promising therapy for recovering voluntary motor function after SCI. Our pilot data shows that this same intervention may be able to restore autonomic control of blood pressure. My fellowship work aimed to: a) utilize targeted spinal electrical stimulation to acutely improve autonomic/cardiovascular function after SCI; b) employ chronic spinal electrical stimulation to neurorehabilitate autonomic control of blood pressure after SCI; and c) understand the mechanisms underlying neuroprosthetic-mediated improvements of autonomic function after SCI.
This proposal seeks to address this important knowledge gap. The overall OBJECTIVES of this fellowship were to understand the sympathetic nervous system connectome, reveal how a clinically- relevant SCI alters these circuits, and harness this knowledge to develop a neurorehabilitation paradigm grounded in the fundamental mechanisms of epidural electrical spinal cord stimulation.
This proposal seeks to address this important knowledge gap. The overall OBJECTIVES of this fellowship were to understand the sympathetic nervous system connectome, reveal how a clinically- relevant SCI alters these circuits, and harness this knowledge to develop a neurorehabilitation paradigm grounded in the fundamental mechanisms of epidural electrical spinal cord stimulation.
Over the past 2 years my main research focus has been our ongoing work developing an electrical autonomic neuroprosthesis that delivers electrical stimulation in closed loop to stabilize hemodynamics. I examined previous studies that showed epidural electrical stimulation of the spinal cord transforms spinal circuits from a hypoactive to a highly active state, and can reinstate spinal circuit dynamics to restore walking after paralysis. We leveraged these concepts to develop epidural electrical stimulation protocols that restored hemodynamic stability after spinal cord injury. I established a new preclinical model that enabled the dissection of the topology and dynamics of sympathetic circuits engaged by epidural electrical stimulation (EES). I incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic hemodynamic regulator operating in closed-loop. This neuroprosthetic baroreflex controlled hemodynamics for extended periods of time in rodents, non-human primates, and humans, both after acute and chronic SCI. These results were published in Nature as a full article (Squair et al., Nature, 2021). We also published all our procedures in the form of open-source protocols for the field (Soriano*, Hudelle*, Squair* et al., Nature Protocols, in press).
We thus developed and validated what we termed a “neuroprosthetic baroreflex” that uses EES of the lower thoracic spinal cord to achieve ultrafast and precise control of hemodynamics. This development is based on a translational framework including rodent models, NHP models and clinical studies. This framework enabled us to understand the mechanisms of this treatment, and thus optimize the features of neuroprosthetic baroreflex. We then scaled up and validated the efficacy of our research-grade neuroprosthetic baroreflex technology in three rhesus monkeys. Finally, we validated all the key features of the neuroprosthetic baroreflex in one human who suffered severe orthostatic hypotension due to a clinically complete cervical SCI. This translational framework captures the core philosophy of .NeuroRestore, the center that the host supervisor (Courtine, Bloch) leads. We foster a continuing reciprocal transfer of ideas between our platforms in rodent models, NHP models, and clinical studies; in addition to tight collaborations with industries. This philosophy is uniquely suited to translate our ideas and technologies into real-life treatments. This transfer of ideas across the entire translational spectrum and to industry will continue to support the optimization of this treatment for clinical use. We have repeatedly experienced this bidirectional exchange during the development of our treatment to restore walking after paralysis.
The completion of the work contained within this fellowship established the necessary evidence to bring the neuroprosthetic baroreflex to clinical trials: Importantly, the results of the pilot clinical trial will inform the methodology for such a large-scale clinical trial with sufficient power to assess the immediate efficacy of the neuroprosthetic baroreflex, and the long-term efficacy of the neuroprosthetic baroreflex combined with autonomic neurorehabilitation.
We envision that the neuroprosthetic baroreflex combined with autonomic neurorehabilitation will become a new treatment to manage hemodynamic instability after SCI in people who do not respond to conservative management.
We thus developed and validated what we termed a “neuroprosthetic baroreflex” that uses EES of the lower thoracic spinal cord to achieve ultrafast and precise control of hemodynamics. This development is based on a translational framework including rodent models, NHP models and clinical studies. This framework enabled us to understand the mechanisms of this treatment, and thus optimize the features of neuroprosthetic baroreflex. We then scaled up and validated the efficacy of our research-grade neuroprosthetic baroreflex technology in three rhesus monkeys. Finally, we validated all the key features of the neuroprosthetic baroreflex in one human who suffered severe orthostatic hypotension due to a clinically complete cervical SCI. This translational framework captures the core philosophy of .NeuroRestore, the center that the host supervisor (Courtine, Bloch) leads. We foster a continuing reciprocal transfer of ideas between our platforms in rodent models, NHP models, and clinical studies; in addition to tight collaborations with industries. This philosophy is uniquely suited to translate our ideas and technologies into real-life treatments. This transfer of ideas across the entire translational spectrum and to industry will continue to support the optimization of this treatment for clinical use. We have repeatedly experienced this bidirectional exchange during the development of our treatment to restore walking after paralysis.
The completion of the work contained within this fellowship established the necessary evidence to bring the neuroprosthetic baroreflex to clinical trials: Importantly, the results of the pilot clinical trial will inform the methodology for such a large-scale clinical trial with sufficient power to assess the immediate efficacy of the neuroprosthetic baroreflex, and the long-term efficacy of the neuroprosthetic baroreflex combined with autonomic neurorehabilitation.
We envision that the neuroprosthetic baroreflex combined with autonomic neurorehabilitation will become a new treatment to manage hemodynamic instability after SCI in people who do not respond to conservative management.
SCI leads to severe hemodynamic instability that dramatically impacts quality of life and increases mortality and morbidity. We exposed the mechanisms through which EES of the caudal thoracic spinal cord can modulate blood pressure. This knowledge translated into a comprehensive engineering approach that controls hemodynamics in closed-loop after SCI in rats, NHPs, and humans. Our next steps are to prepare the translational pathway for the neuroprosthetic baroreflex and autonomic neurorehabilitation to become a new therapy for orthostatic hypotension and autonomic dysreflexia after SCI.
Why would this solution have such a profound impact on hemodynamic dysfunction for people with SCI? Once people with SCI have stabilized and are moved to a rehabilitation centre, and then into the community, clinicians have turned to various methods to manage the frequent blood pressure drops and spikes experienced by people with SCI. These methods include abdominal binding, compression stockings, high-fluid diet, and pharmacology. While these measures may provide some relief from the symptoms associated with orthostatic hypotension and autonomic dysreflexia in mild cases, the vast majority of people remain symptomatic and at increased risk for cardiovascular disease. Here we developed a new solution to manage this hemodynamic instability after SCI. This engineering- based solution leverages our understanding of the mechanisms through which EES modulates the sympathetic circuits. We showed that the neuroprosthetic baroreflex controls blood pressure during extreme perturbations of the cardiovascular system.
We suggest that achieving robust hemodynamic stability in people with SCI is one of the most promising ways to both optimize neurological recovery (in the acute phase) and to reduce secondary medical complications in the chronic phase.
Why would this solution have such a profound impact on hemodynamic dysfunction for people with SCI? Once people with SCI have stabilized and are moved to a rehabilitation centre, and then into the community, clinicians have turned to various methods to manage the frequent blood pressure drops and spikes experienced by people with SCI. These methods include abdominal binding, compression stockings, high-fluid diet, and pharmacology. While these measures may provide some relief from the symptoms associated with orthostatic hypotension and autonomic dysreflexia in mild cases, the vast majority of people remain symptomatic and at increased risk for cardiovascular disease. Here we developed a new solution to manage this hemodynamic instability after SCI. This engineering- based solution leverages our understanding of the mechanisms through which EES modulates the sympathetic circuits. We showed that the neuroprosthetic baroreflex controls blood pressure during extreme perturbations of the cardiovascular system.
We suggest that achieving robust hemodynamic stability in people with SCI is one of the most promising ways to both optimize neurological recovery (in the acute phase) and to reduce secondary medical complications in the chronic phase.